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Abilify Maintena (aripiprazole) – Summary of product characteristics - N05AX12

Updated on site: 11-Jul-2017

Medication nameAbilify Maintena
ATC CodeN05AX12
Substancearipiprazole
ManufacturerOtsuka Pharmaceutical Europe Ltd

1.NAME OF THE MEDICINAL PRODUCT

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection Each vial contains 300 mg aripiprazole.

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection Each vial contains 400 mg aripiprazole.

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Each pre-filled syringe contains 300 mg aripiprazole.

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Each pre-filled syringe contains 400 mg aripiprazole.

After reconstitution each ml of suspension contains 200 mg aripiprazole.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection Powder and solvent for prolonged-release suspension for injection

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Powder: white to off-white

Solvent: clear solution

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.

4.2Posology and method of administration

Posology

For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena.

The recommended starting and maintenance dose of Abilify Maintena is 400 mg.

Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).

After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.

If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.

Missed doses

 

Missed doses

If 2nd or 3rd dose is missed and time

Action

since last injection is:

 

> 4 weeks and < 5 weeks

The injection should be administered as soon as possible and

 

then resume monthly injection schedule.

> 5 weeks

Concomitant oral aripiprazole should be restarted for 14 days

 

with next administered injection and then resume monthly

 

injection schedule.

If 4th or subsequent doses are missed

Action

(i.e., after attainment of steady state)

 

and time since last injection is:

 

> 4 weeks and < 6 weeks

The injection should be administered as soon as possible and

 

then resume monthly injection schedule.

> 6 weeks

Concomitant oral aripiprazole should be restarted for 14 days

 

with next administered injection and then resume monthly

 

injection schedule.

Special populations

 

Elderly

The safety and efficacy of Abilify Maintena in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4).

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients requiring cautious dosing, oral formulation should be preferred (see section 5.2).

Known CYP2D6 poor metabolisers

In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg (see section 4.5).

Dose adjustments due to interactions

Dosage adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose (see section 4.5). In case of

adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Dose adjustments of Abilify Maintena in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

 

Adjusted dose

 

 

Patients taking 400 mg of Abilify Maintena

 

Strong CYP2D6 or strong CYP3A4 inhibitors

300 mg

Strong CYP2D6 and strong CYP3A4 inhibitors

200 mg*

CYP3A4 inducers

Avoid use

Patients taking 300 mg of Abilify Maintena

 

Strong CYP2D6 or strong CYP3A4 inhibitors

200 mg*

Strong CYP2D6 and strong CYP3A4 inhibitors

160 mg*

CYP3A4 inducers

Avoid use

*200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Abilify Maintena powder and solvent for prolonged-release suspension for injection.

Paediatric population

The safety and efficacy of Abilify Maintena in children and adolescents aged 0-17 years have not been established. No data are available.

Method of administration

Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.

Abilify Maintena powder and solvent for prolonged-release suspension for injection

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial.

Abilify Maintena powder and solvent for prolonged-release suspension for injection in pre-filled syringe

The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe.

The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.

Gluteal muscle administration

The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m2), a 50 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.

Deltoid muscle administration

The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used. Deltoid injections should be alternated between the two deltoid muscles.

The powder and solvent vials and the pre-filled syringe are for single-use only.

Full instructions for use and handling of Abilify Maintena are provided in the package leaflet (information intended for healthcare professionals).

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Use in patients who are in an acutely agitated or severely psychotic state

Abilify Maintena should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high risk patients should accompany antipsychotic treatment.

Cardiovascular disorders

Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken (see section 4.8).

QT prolongation

In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation (see section 4.8).

Tardive dyskinesia

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient

develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including aripiprazole, must be discontinued (see section 4.8).

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8).

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8).

Cerebrovascular adverse reactions

In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-treated patients in these trials. This difference was not

statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose- response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8).

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic medicines, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicines are not available to allow direct comparisons. Patients treated with any antipsychotic medicinal products, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary

adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (see section 4.8).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling

Post-marketing reports of pathological gambling have been reported among patients prescribed oral aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully (see section 4.8).

4.5Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole.

Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.

Potential for other medicinal products to affect aripiprazole

Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Quinidine and other strong CYP2D6 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine)

increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro- aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Other strong inhibitors

of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied (see section 4.2).

Ketoconazole and other strong CYP3A4 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole)

increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro- aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant

use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should, therefore, be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the dose prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with this medicinal product, modest increases in plasma aripiprazole concentrations may be expected.

Carbamazepine and other CYP3A4 inducers

Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when oral aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with oral aripiprazole alone.Concomitant administration of Abilify Maintena and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects. The concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.

Valproate and lithium

When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations, and, therefore, no dose adjustment is necessary when either valproate or lithium is administered with Abilify Maintena.

Potential for aripiprazole to affect other medicinal products

In clinical studies, oral doses of 10-30 mg/day of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, Abilify Maintena is unlikely to cause clinically important medicinal product interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with lamotrigine, dextromethorphan, warfarin, omeprazole, escitalopram, or venlafaxine there was no clinically important change in concentrations of these medicinal products. Thus, no dosage adjustment of these medicinal products is required when co-administered with Abilify Maintena.

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

4.6Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Abilify Maintena. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus.

Prescribers need to be aware of the long-acting properties of Abilify Maintena.

New-born infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, new-born infants should be monitored carefully (see section 4.8).

Breast-feeding

Aripiprazole is excreted in human milk. A decision must be made whether to discontinue breast- feeding or to discontinue/abstain from Abilify Maintena therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Aripiprazole did not impair fertility based on data from reproductive toxicity studies.

4.7Effects on ability to drive and use machines

Aripiprazole can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to this medicinal product is known.

4.8Undesirable effects

Summary of the safety profile

The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind, long-term trials of Abilify Maintena were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %), and injection site pain (5.1 %).

Tabulated list of adverse reactions

The incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known".

 

Common

Uncommon

Not known

 

 

 

 

Blood and

 

Neutropenia

Leukopenia

lymphatic

 

Anaemia

 

system

 

Thrombocytopenia

 

disorders

 

Neutrophil count decreased

 

 

 

White blood cell count

 

 

 

decreased

 

Immune

 

Hypersensitivity

Allergic reaction (e.g.

system

 

 

anaphylactic reaction,

disorders

 

 

angioedema including swollen

 

 

 

tongue, tongue oedema, face

 

 

 

oedema, pruritus, or urticaria)

Endocrine

 

Blood prolactin decreased

Diabetic hyperosmolar coma

disorders

 

Hyperprolactinaemia

Diabetic ketoacidosis

Metabolism

Weight

Hyperglycaemia

Anorexia

and nutrition

increased

Hypercholesterolaemia

Hyponatraemia

disorders

Diabetes

Hyperinsulinaemia

 

 

mellitus

Hyperlipidaemia

 

 

Weight

Hypertriglyceridaemia

 

 

decreased

Appetite disorder

 

 

 

 

 

 

Common

Uncommon

Not known

 

 

 

 

Psychiatric

Agitation

Suicidal ideation

Completed suicide

disorders

Anxiety

Psychotic disorder

Suicide attempt

 

Restlessness

Hallucination

Pathological gambling

 

Insomnia

Delusion

Nervousness

 

 

Hypersexuality

Aggression

 

 

Panic reaction

 

 

 

Depression

 

 

 

Affect lability

 

 

 

Apathy

 

 

 

Dysphoria

 

 

 

Sleep disorder

 

 

 

Bruxism

 

 

 

Libido decreased

 

 

 

Mood altered

 

Nervous

Extrapyramidal

Dystonia

Neuroleptic malignant syndrome

system

disorder

Tardive dyskinesia

Grand mal convulsion Serotonin

disorders

Akathisia

Parkinsonism

syndrome

 

Tremor

Movement disorder

Speech disorder

 

Dyskinesia

Psychomotor hyperactivity

 

 

Sedation

Restless legs syndrome

 

 

Somnolence

Cogwheel rigidity

 

 

Dizziness

Hypertonia

 

 

Headache

Bradykinesia

 

 

 

Drooling

 

 

 

Dysgeusia

 

 

 

Parosmia

 

 

 

 

 

Eye disorders

 

Oculogyric crisis

 

 

 

Vision blurred

 

 

 

Eye pain

 

 

 

Diplopia

 

Cardiac

 

Ventricular extrasystoles

Sudden unexplained death

disorders

 

Bradycardia

Cardiac arrest

 

 

Tachycardia

Torsades de pointes Ventricular

 

 

Electrocardiogram T wave

arrhythmias

 

 

amplitude decreased

QT prolongation

 

 

Electrocardiogram abnormal

 

 

 

Electrocardiogram T wave

 

 

 

inversion

 

Vascular

 

Hypertension

Syncope

disorders

 

Orthostatic hypotension

Venous thromboembolism

 

 

Blood pressure increased

(including pulmonary embolism

 

 

 

and deep vein thrombosis)

 

 

 

 

Respiratory,

 

Cough

Oropharyngeal spasm

thoracic and

 

Hiccups

Laryngospasm

mediastinal

 

 

Aspiration pneumonia

disorders

 

 

 

Gastrointesti

Dry mouth

Gastrooesophageal reflux

Pancreatitis

nal disorders

 

disease

Dysphagia

 

 

Dyspepsia

 

 

 

Vomiting

 

 

 

Diarrhoea

 

 

 

Nausea

 

 

 

Abdominal pain upper

 

 

Common

Uncommon

Not known

 

 

 

 

 

 

Abdominal discomfort

 

 

 

Constipation

 

 

 

Frequent bowel movement

 

 

 

Salivary hypersecretion

 

Hepatobiliary

 

Liver function test abnormal

Hepatic failure

disorders

 

Hepatic enzyme increased

Jaundice

 

 

Alanine aminotransferase

Hepatitis

 

 

increased

Alkaline phosphatase increased

 

 

Gamma-glutamyl transferase

 

 

 

increased

 

 

 

Blood bilirubin increased

 

 

 

Aspartate aminotransferase

 

 

 

increased

 

Skin and

 

Alopecia

Rash

subcutaneous

 

Acne

Photosensitivity reaction

tissue

 

Rosacea

Hyperhidrosis

disorders

 

Eczema

 

 

 

Skin induration

 

Musculoskele

Musculoskeletal

Muscle rigidity

Rhabdomyolysis

tal and

stiffness

Muscle spasms

 

connective

 

Muscle twitching

 

tissue

 

Muscle tightness

 

disorders

 

Myalgia

 

 

 

Pain in extremity

 

 

 

Arthralgia

 

 

 

Back pain

 

 

 

Joint range of motion

 

 

 

decreased

 

 

 

Nuchal rigidity

 

 

 

Trismus

 

Renal and

 

Nephrolithiasis

Urinary retention

urinary

 

Glycosuria

Urinary incontinence

disorders

 

 

 

Pregnancy,

 

 

Drug withdrawal syndrome

puerperium

 

 

neonatal (see section 4.6)

and perinatal

 

 

 

conditions

 

 

 

Reproductive

Erectile

Galactorrhoea

Priapism

system and

dysfunction

Gynaecomastia

 

breast

 

Breast tenderness

 

disorders

 

Vulvovaginal dryness

 

General

Injection site

Pyrexia

Temperature regulation disorder

disorders and

pain

Asthenia

(e.g. hypothermia, pyrexia)

administratio

Injection site

Gait disturbance

Chest pain

n site

induration

Chest discomfort

Peripheral oedema

conditions

Fatigue

Injection site reaction

 

 

 

Injection site erythema

 

 

 

Injection site swelling

 

 

 

Injection site discomfort

 

 

 

Injection site pruritus

 

 

 

Thirst

 

 

 

Sluggishness

 

 

Common

Uncommon

Not known

 

 

 

 

Investigations

Blood creatine

Blood glucose increased

Blood glucose fluctuation

 

phosphokinase

Blood glucose decreased

 

 

increased

Glycosylated haemoglobin

 

 

 

increased

 

 

 

Waist circumference

 

 

 

increased

 

 

 

Blood cholesterol decreased

 

 

 

Blood triglycerides decreased

 

 

 

 

 

Description of selected adverse reactions

Injection site reactions

During the double-blind, controlled phases of the two long-term trials, injection site reactions were observed; those seen were generally mild to moderate in severity, and resolved over time. Injection site pain (incidence 5.1 %), had a median onset on day 2 after the injection and a median duration of 4 days.

In an open label study comparing bioavailability of Abilify Maintena administered in the deltoid or gluteal muscle, injection site related reactions were slightly more frequent in the deltoid muscle. The majority were mild and improved on subsequent injections. When compared to studies where Abilify Maintena was injected in the gluteal muscle, repeated occurrence of injection site pain was more frequent in the deltoid muscle.

Leukopenia

Neutropenia has been reported in the clinical program with Abilify Maintena and typically started around day 16 after first injection, and lasted a median of 18 days.

Extrapyramidal Symptoms (EPS)

In trials in stable patients with schizophrenia, Abilify Maintena was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was the most frequently observed symptom (8.2 %) and typically started around day 10 after first injection, and lasted a median of 56 days. Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia. Parkinsonism events followed in frequency of 6.9 % for Abilify Maintena, 4.15 % for oral aripiprazole 10-30 mg tablets and 3.0 % for placebo, respectively.

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.

Weight

During the Double-blind, Active-controlled Phase of the 38-week long-term trial, the incidence of

weight gain of 7 % from baseline to last visit was 9.5 % for Abilify Maintena and 11.7 % for the oral aripiprazole tablets 10-30 mg. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena and 4.5 % for oral aripiprazole tablets 10-30 mg. During the Double-

blind, Placebo-controlled Phase of the 52-week long-term trial, the incidence of weight gain of 7 % from baseline to last visit was 6.4 % for Abilify Maintena and 5.2 % for placebo. The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena and 6.7 % for placebo.

During double-blind treatment, mean change in body weight from baseline to last visit was -0.2 kg for Abilify Maintena and -0.4 kg for placebo (p = 0.812).

Prolactin

In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

No cases of overdose associated with adverse reactions were reported in clinical studies with Abilify Maintena. Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel. Following any confirmed or suspected accidental overdose/inadvertent intravenous administration, close observation of the patient is needed and if any potentially medically serious sign or symptom develops, monitoring, which should include continuous electrocardiographic monitoring, is required. The medical supervision and monitoring should continue until the patient recovers.

A simulation of dose dumping showed that the predicted median aripiprazole concentration reaches a peak of 4500 ng/ml or approximately 9 times the upper therapeutic range. In case of dose dumping, aripiprazole concentrations are predicted to descend rapidly to the upper limit of the therapeutic window after approximately 3 days. By the 7th day, the median aripiprazole concentrations further decline to concentrations following an IM depot dose with no dose dumping. While overdose is less likely with parenteral than oral medicinal products, reference information for oral aripiprazole overdose is presented below.

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg

(41 times highest recommended daily aripiprazole dose) with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.

Management of overdose

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore, cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.

Haemodialysis

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12

Mechanism of action

It has been proposed that aripiprazole’s efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and has moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for cholinergic muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole oral doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Maintenance treatment of schizophrenia in adults

The efficacy of Abilify Maintena in the maintenance treatment of patients with schizophrenia was established in two randomised, double-blind, long-term trials.

The pivotal trial was a 38 week, randomised, double-blind, active-controlled trial designed to establish the efficacy, safety, and tolerability of this medicinal product administered as monthly injections compared to once daily oral aripiprazole tablets 10-30 mg as maintenance treatment in adult patients with schizophrenia. This trial consisted of a screening phase and 3 treatment phases: Conversion Phase, Oral Stabilisation Phase, and Double-blind, Active-controlled Phase.

Six-hundred and sixty two patients eligible for the 38-week Double-blind, Active-controlled Phase were randomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) Abilify Maintena 2) the stabilisation dose of oral aripiprazole 10-30 mg, or 3) aripiprazole Long- Acting Injectable 50 mg/25 mg. The aripiprazole Long-Acting Injectable 50 mg/25 mg dose was included as a low dose aripiprazole to test assay sensitivity for the non-inferiority design.

The results of analysis of the primary efficacy endpoint, the estimated proportion of patients experiencing impending relapse by end of Week 26 of the Double-blind, Active-controlled Phase, showed that Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10-30 mg. The estimated relapse rate by end of Week 26 was 7.12 % for Abilify Maintena , and 7.76 % for oral aripiprazole tablets 10-30 mg , a difference of -0.64 %.

The 95 % CI (-5.26, 3.99) for the difference in the estimated proportion of patients experiencing impending relapse by end of Week 26 excluded the predefined non-inferiority margin, 11.5 %. Therefore, Abilify Maintena is non-inferior to aripiprazole oral tablets 10-30 mg.

The estimated proportion of patients experiencing impending relapse by end of Week 26 for Abilify Maintena was 7.12 %, which was statistically significantly lower than in aripiprazole Long-Acting Injectable 50 mg/25 mg (21.80 %; p = 0.0006). Thus, superiority of Abilify Maintena over the aripiprazole Long-Acting Injectable 50 mg/25 mg was established and the validity of the trial design was confirmed.

The Kaplan-Meier curves of the time from randomisation to impending relapse during the 38-week, Double-blind, Active-controlled Phase for Abilify Maintena, oral aripiprazole 10-30 mg, and aripiprazole Long-Acting Injectable 50 mg/25 mg are shown in Figure 1.

Figure 1 Kaplan-Meier Product Limit Plot for Time to Exacerbation of Psychotic Symptoms/Impending Relapse

relapse

0.8

impending

 

1.0

free of

0.6

subjectsof

0.4

 

Proportion

0.2

0.0

 

IMD 400/ 300 mg

ARIP 10-30 mg IMD 50/25 mg

Log-RankTest

ARIP IMD 400/300 mgvs. ARIP 10-30mg:p value 0.9920

ARIP IMD 400/300 mgvs. ARIP IMD 50/25 mg: p value< 0.0001

Numbers of Subjectsat Risk

ARIP IMD400/300 mg ARIP 10-30 mg

ARIP IMD50/25 mg

Days fromRandomization

NOTE: ARIP IMD 400/300 mg = Abilify Maintena;ARIP 10-30 mg = oral aripiprazole; ARIP IMD 50/25 mg = Long-acting Injectable

Further, the non-inferiority of Abilify Maintena compared to oral aripiprazole 10-30 mg is supported by the results of the analysis of the Positive and Negative Syndrome Scale score (PANSS).

Table 1 PANSS Total Score – Change From Baseline to Week 38-LOCF: Randomised Efficacy Sample a, b

PANSS Total Score – Change From Baseline to Week 38-LOCF:

Randomised Efficacy Sample a, b

 

Abilify Maintena

Oral aripiprazole

Aripiprazole Long-Acting

 

400 mg/300 mg

10-30 mg/day

Injectable

 

50 mg/25 mg

 

(n = 263)

(n = 266)

(n = 131)

Mean baseline (SD)

57.9 (12.94)

56.6 (12.65)

56.1 (12.59)

 

 

 

 

Mean change (SD)

-1.8 (10.49)

0.7 (11.60)

3.2 (14.45)

 

 

 

 

P-value

NA

0.0272

0.0002

a:Negative change in score indicates improvement.

b:Only patients having both baseline and at least one post baseline were included. P-values were derived from comparison for change from baseline within analysis of covariance model with treatment as term and baseline as covariate.

The second trial was a 52-week, randomised, withdrawal, double-blind, trial conducted in US adult patients with a current diagnosis of schizophrenia. This trial consisted of a screening phase and

4 treatment phases: Conversion, Oral Stabilisation, Abilify Maintena Stabilisation, and Double-blind Placebo-controlled. Patients fulfilling the oral stabilisation requirement in the Oral Stabilisation Phase were assigned to receive, in a single-blind fashion, Abilify Maintena and began an Abilify Maintena Stabilisation Phase for a minimum of 12 weeks and a maximum of 36 weeks. Patients eligible for the Double-blind, Placebo-controlled Phase were randomly assigned in a 2:1 ratio to double-blind treatment with Abilify Maintena or placebo, respectively.

The final efficacy analysis included 403 randomised patients and 80 exacerbations of psychotic symptoms/impending relapse events. In the placebo group 39.6 % of the patients had progressed to impending relapse, whilst in the Abilify Maintena group impending relapse occurred in 10 % of the patients; thus patients in the placebo group had a 5.03-fold greater risk of experiencing impending relapse.

Prolactin

In the Double-blind, Active-controlled Phase of the 38-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena (−0.33 ng/ml) compared with a mean increase in oral aripiprazole tablets 10-30 mg (0.79 ng/ml; p < 0.01). The incidence of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) at any assessment was 5.4 % compared with 3.5 % of the patients on oral aripiprazole tablets 10-30 mg.

Male patients generally had a higher incidence than female patients in each treatment group.

In the Double-blind Placebo-controlled Phase of the 52-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena (−0.38 ng/ml) compared with a mean increase in placebo (1.67 ng/ml). The incidences of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) was 1.9 % compared to 7.1 % for placebo patients.

Acute treatment of schizophrenia in adults

The efficacy of Abilify Maintena in acutely relapsed adult patients with schizophrenia was established in a short-term (12-week), randomised, double-blind, placebo-controlled trial (n = 339).

The primary endpoint (change in PANSS total score from baseline to week 10) showed superiority of Abilify Maintena (n = 167) over placebo (n = 172).

Similar to the PANSS Total Score, both the PANSS positive and negative subscale scores also showed an improvement (decrease) from baseline over time.

Table 2 PANSS Total Score – Change From Baseline to week 10: Randomised Efficacy Sample

PANSS Total Score – Change From Baseline to Week 10:

Randomised Efficacy Sample a

 

Abilify Maintena

Placebo

 

400 mg/300 mg

 

Mean baseline (SD)

102.4 (11.4)

103.4 (11.1)

 

n = 162

n = 167

LS Mean change (SE)

-26.8 (1.6)

-11.7 (1.6)

 

n = 99

n = 81

P-value

< 0.0001

 

Treatment differenceb (95 % CI)

-15.1 (-19.4, -10.8)

 

aData were analysed using a mixed model repeated measures (MMRM) approach. The analysis included only subjects who were randomly assigned to treatment, given at least one injection, had baseline and at least one post-baseline efficacy assessment.

bDifference (Abilify Maintena minus placebo) in least squares mean change from baseline.

Abilify Maintena also showed statistically significant improvement in symptoms represented by CGIS score change from baseline to week 10.

Personal and social functioning were evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g. work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours. There was a statistically significant treatment difference in favour of Abilify Maintena 400 mg/300 mg compared to placebo at week 10 (+7.1, p < 0.0001, 95 % CI: 4.1, 10.1 using an ANCOVA model (LOCF)).

The safety profile was consistent with that known to Abilify Maintena. Nevertheless, there were differences from what has been observed with maintenance use in the treatment of schizophrenia. In a short-term (12-week), randomised, double-blind, placebo-controlled trial with Abilify Maintena

400 mg/300 mg treated subjects the symptoms which had at least twice the incidence of placebo were

increased weight and akathisia. The incidence of weight gain of ≥ 7 % from baseline to last visit (week 12) was 21.5 % for Abilify Maintena compared with the placebo group 8.5 %. Akathisia was the most frequently observed EPS symptom (Abilify Maintena 11.4 % and placebo group 3.5 %).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Abilify Maintena in all subsets of the paediatric population in schizophrenia (see section 4.2).

5.2Pharmacokinetic properties

Absorption

Aripiprazole absorption into the systemic circulation is slow and prolonged following Abilify Maintena administration due to low solubility of aripiprazole particles.The average absorption half-life of Abilify Maintena is 28 days. Absorption of aripiprazole from the IM depot formulation was complete relative to the IM standard (immediate-release) formulation. The dose adjusted Cmax values for the depot formulation were approximately 5 % of Cmax from IM standard formulation.Following a single dose administration of Abilify Maintena in the deltoid and gluteal muscle, the extent of absorption (AUC) was similar for both injection sites, but the rate of absorption (Cmax) was higher following administration to the deltoid muscle.Following multiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to a maximum plasma concentration at a median tmax

of 7 days for the gluteal muscle and 4 days for the deltoid muscle.Steady state concentrations for the typical subject were attained by the fourth dose for both sites of administration.Less than dose- proportional increases in aripiprazole and dehydro-aripiprazole concentrations and AUC parameters are observed after monthly Abilify Maintena injections of 300 mg to 400 mg.

Distribution

Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99 % bound to serum proteins, binding primarily to albumin.

Biotransformation

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. After multiple dose administration of Abilify Maintena, dehydro-aripiprazole, the active metabolite, represents about 29.1-32.5 % of aripiprazole AUC in plasma.

Elimination

After administration of multiple dose of 400 mg or 300 mg of Abilify Maintena, the mean aripiprazole terminal elimination half-life is respectively 46.5 and 29.9 days presumably due to absorption rate- limited kinetics. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27 % of the administered radioactivity was recovered in the urine and approximately 60 % in the faeces. Less than 1 % of unchanged aripiprazole was excreted in the urine and approximately 18 % was recovered unchanged in the faeces.

Pharmacokinetics in special patient groups

CYP2D6 poor metabolisers

Based on population pharmacokinetic evaluation of Abilify Maintena, the total body clearance of aripiprazole was 3.71 L/h in extensive metabolisers of CYP2D6 and approximately 1.88 L/h

(approximately 50 % lower) in poor metabolisers of CYP2D6 (for dose recommendation, see section 4.2).

Elderly

After oral administration of aripiprazole, there are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects. Similarly, there was no detectable effect of age in a population pharmacokinetic analysis of Abilify Maintena in schizophrenia patients.

Gender

After oral administration of aripiprazole, there are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects. Similarly, there was no clinically relevant effect of gender in a population pharmacokinetic analysis of Abilify Maintena in clinical trials in patients with schizophrenia.

Smoking

Population pharmacokinetic evaluation of oral aripiprazole has revealed no evidence of clinically relevant effects from smoking on the pharmacokinetics of aripiprazole.

Race

Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.

Renal impairment

In a single-dose study with oral administration of aripiprazole, the pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to that in young healthy subjects.

Hepatic impairment

A single-dose study with oral administration of aripiprazole to subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

5.3Preclinical safety data

The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels. With intramuscular injection, however an inflammatory response was seen at the injection site, and consisted of granulomatous inflammation, foci (deposited drug), cellular infiltrates, oedema (swelling) and, in monkeys, fibrosis. These effects gradually resolved with discontinuation of dosing.

Non-clinical safety data for orally administered aripiprazole reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Oral aripiprazole

For oral aripiprazole, toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity in rats after 104 weeks of oral administration at approximately 3 to 10 times the mean steady-state AUC at the maximum recommended human dose and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at approximately 10 times the mean steady-state AUC at the maximum recommended human dose. The highest non-tumorigenic exposure in female rats was approximately 7 times the human exposure at the recommended dose.

An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy-metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to

125 mg/kg/day or approximately16 to 81 times the maximum recommended human dose based on mg/m2.

However, the concentrations of the sulphate conjugates of hydroxy-aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6 % of the bile concentrations found in the monkeys in the 39-week study and are well below (6 %) their limits of in vitro solubility.

In repeated dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse events on development.

Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non- genotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies.

Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in sub-therapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures approximately 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Powder

Carmellose sodium

Mannitol

Sodium dihydrogen phosphate monohydrate

Sodium hydroxide

Solvent

Water for injections

6.2Incompatibilities

Not applicable

6.3Shelf life

3 years

After reconstitution

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From a microbiological point of view, unless the method of opening/ reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of user. Shake the vial vigorously for at least 60 seconds to re-suspend prior to injection. Do not store the reconstituted suspension in the syringe.

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

If the injection is not performed immediately after reconstitution, the syringe can be kept below 25 °C for up to 2 hours. Shake the syringe vigorously for at least 20 seconds to re-suspend prior to injection if the syringe has been left for more than 15 minutes.

6.4Special precautions for storage

Do not freeze.

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

Keep the syringe in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5Nature and contents of container

Vial

Type-I glass vial stoppered with a laminated rubber stopper and sealed with a flip-off aluminium cap.

Solvent

2 ml Type-1 glass vial stoppered with a laminated rubber stopper and sealed with a flip-off aluminium cap.

Single pack

Each single pack containing one vial of powder, 2 ml vial of solvent, one 3 ml luer lock syringe with pre-attached 38 mm (1.5 inch) 21 gauge, hypodermic safety needle with needle protection device, one 3 ml disposable syringe with luer lock tip, one vial adapter and three hypodermic safety needles: one 25 mm (1 inch) 23 gauge, one 38 mm (1.5 inch) 22 gauge and one 50 mm (2 inch) 21 gauge.

Multipack

Bundle pack of 3 single packs.

Pre-filled syringe

Type-I glass pre-filled syringe containing powder in the front chamber and solvent in the rear chamber.

Single pack

Each single pack containing one pre-filled syringe, and three hypodermic safety needles: one 25 mm (1 inch) 23 gauge, one 38 mm (1.5 inch) 22 gauge and one 50 mm (2 inch) 21 gauge.

Multipack

Bundle pack of 3 single packs.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Full instructions for use and handling of Abilify Maintena are provided in the package leaflet (information intended for healthcare professionals).

7.MARKETING AUTHORISATION HOLDER

Otsuka Pharmaceutical Europe Ltd.

Gallions, Wexham Springs, Framewood Road,

Wexham, SL3 6PJ - United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection EU/1/13/882/001

EU/1/13/882/003

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection EU/1/13/882/002

EU/1/13/882/004

Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

EU/1/13/882/005

EU/1/13/882/007

Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe

EU/1/13/882/006

EU/1/13/882/008

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15. November 2013

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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